Randomized Trial of Induction Therapies in High Immunological Risk Kidney Transplant Recipients

Optimal induction regimens for patients at high risk for antibody and/or cell-mediated
rejection have not been established. This pilot, prospective, randomized study evaluated
addition of B cell/plasma cell-targeting agents to T cell-based induction with rabbit
antithymocyte globulin (rATG) in high immunologic risk renal transplant recipients. Patients
were randomized to induction with rATG, rATGþrituximab, rATGþbortezomib or
rATGþrituximabþbortezomib.

Inclusion Criteria

Each patient must meet all of the following inclusion criteria to be enrolled in the
study:

- Voluntary written informed consent before performance of any study-related procedure
not part of normal medical care, with the understanding that consent may be withdrawn
by the subject at any time without prejudice to future medical care.

- Patient is between the 18 and 65 years of age, inclusive.

- Patient is considered high risk for acute rejection based on any one of the
following:

- Patient has a current Cytotoxic PRA≥ 20% or a peak Cytotoxic PRA ≥50%

- Patient has a T or B-cell positive crossmatch (by flow cytometry) with confirmed
donor-specific antibodies on solid-phase assay.

- Historical positive serologic or cytotoxic crossmatch or DSA to donor

- Prior allograft loss with a history of more than one acute rejection episode.

- Female subject is either postmenopausal for at least 1 year prior to initiation of
study treatment, is surgically sterilized, or if of childbearing potential, agrees to
practice 2 effective methods of contraception from the time of signing the informed
consent form through 30 days after the last dose of bortezomib, or agrees to
completely abstain from heterosexual intercourse. Women of childbearing potential
must have a negative serum pregnancy test within the last 48 hours prior to receiving
study medication.

- Male subjects, even if surgically sterilized (i.e. status post-vasectomy) must agree
to 1 of the following: practice effective barrier contraception during the entire
study treatment period and through a minimum of 30 days after the last dose of study
drug, or completely abstain from heterosexual intercourse.

- Patient must have no known contraindications to treatment with bortezomib, rituximab,
or thymoglobulin.

Exclusion Criteria

- Patients that have previously received or are receiving an organ transplant other
than kidney.

- Patient who lost a previous allograft due to recurrence of disease

- Patient is receiving a HLA identical living related kidney transplant

- History of severe allergic or anaphylactic reactions to humanized or murine
monoclonal or polyclonal antibodies

- Patients with an absolute neutrophil count of < 1,000/mm3 or platelet count <
100,000/mm3within 30 days of consent.

- Patient has Grade 2 peripheral neuropathy by CTCAE criteria within 14 days before
enrollment.

- Myocardial infarction within 6 months prior to enrollment or has New York Heart
Association (NYHA) Class III or IV heart failure (see section 9.3), uncontrolled
angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence
of acute ischemia or active conduction system abnormalities. Prior to study entry,
any abnormality on ECG performed within 30 days of consent has to be documented by
the investigator or the patient's transplant nephrologist as not medically relevant.

- Patients who are anti-HIV-positive, or HBsAg-positive or Anti-HCV positive on testing
performed within one year of consent.

- Diagnosed or treated for malignancy within 3 years of enrollment, with the exception
of complete resection of basal cell carcinoma or squamous cell carcinoma of the skin,
an in situ malignancy, or low-risk prostate cancer after curative therapy.

- Patients with current or recent severe systemic infections within the 2 weeks prior
to initiation of study treatment.

- Receipt of a live vaccine within 4 weeks prior to initiation of study treatment.

- Use of other investigational drugs within 30 days or 5 half-lives prior to initiation
of study treatment, whichever is longer

- Evidence of severe liver disease by medical history or physical exam with abnormal
liver profile (aspartate aminotransferase [AST], alanine aminotransferase [ALT] or
total bilirubin > 1.5 times upper limit of normal [ULN]) on testing performed within
30 days of consent.

- Pregnant or nursing (lactating) women and women who might become pregnant during the
study. Female subject is pregnant or breast-feeding. Confirmation that the subject is
not pregnant must be established by a negative serum -human chorionic gonadotropin
pregnancy test result within the last 48 hours prior to receiving study medication.
Pregnancy testing is not required for post-menopausal or surgically sterilized women.

- EBV serologic mismatch (i.e. EBV+ donor transplanted to EBV- recipient)

- CMV serologic mismatch (i.e. CMV+ donor transplanted to CMV- recipient)